A goal of our research is to characterize genetic organization in the domestic cat and to develop genomic resources facilitating and establishing Felis catus as a useful animal model contributing to our understanding of human hereditary disease analogues, neoplasia, genetic factors associated with host response to infectious disease and mammalian genome evolution. In order to map and characterize genes associated with inherited pathologies in the domestic cat which mirror inherited human conditions we have focused on increasing microsatellite density in the genetic map of the cat to increase resolution for mapping of genes associated with inherited and infectious disease.[unreadable] [unreadable] We are completing our third and last genetic linkage map of the domestic cat. The linkage map is being generated in a large multi-generational domestic cat pedigree maintained by the Nestle-Purina Pet Care Company (n=483 informative meioses). Previous first and second generation maps of the cat were generated in an interspecies pedigree between the domestic cat and the Asian leopard cat. Whereas, this gave us the opportunity to map and integrate Type I (coding loci) and Type II (polymorphic microsatellites) loci, the current map will allow us to address whether the hybrid nature of the previous pedigree had an impact on recombination values. The current map will offer single linkage groups of the cat's autosomes and X chromosome at a resolution of approximately 5 cM. Currently 483 microsatellites have been genotyped in the pedigree and have been assembled in linkage groups following two-point linkage. Twelve of the cat's 18 autosomes are now spanned by single linkage groups. With the current availability of unannotated sequence generated in the 2X genome sequence of the cat by NHGRI, we are able to identify and design microsatellites in genomic regions that are currently under-represented or that will "link" groups on one of the six chromosomes with more than a single linkage group. The final map of 19 linkage groups spanning the entire cat genome is projected to be complete in October, 2005.[unreadable] [unreadable] Mapping and Characterization of Genes Associated with Inherited Disease Pathology in Cat Pedigrees with Homology to Human Hereditary Disease:[unreadable] [unreadable] 1. Autosomal recessive retinitis pigmentosa (arRP) is a genetically and clinically heterogeneous and progressive degenerative disorder of the retina, leading usually to severe visual handicap in adulthood. Our collaborator, Dr. Kristina Narfstrom at the Missouri College of Veterinary Medicine, maintains a colony of Abyssinian cats with progressive retinal atrophy (rdAc), a slowly progressive degeneration process of the rod and cone systems with similarities to classical human RP. The Abyssinian cat has the potential of becoming a new and important animal model in the study of hereditary visual cell disease processes. Over 32 candidate genes or genomic regions linked to human RP were genotyped in the rdAc pedigree with highly polymorphic microsatellites and failed to detect linkage to a disease locus. Subsequently, we conducted a full genome screen of the rdAc pedigree with randomly selected polymorphic microsatellites. Linkage has been established to a genomic region with a high logarithm of odds (LOD) score (>15) at a theta of 0. A region of 0 recombination covers a syntenic region of several megabases in the human genome which describes a novel site for RP. The availability of the 2X cat whole genome sequence has enabled us to saturate the region with microsatellites to reduce the disease region as much as possible given and to establish a single nucleotide polymorphism (SNP) map of the region. We are currently sequencing genes with retinal expression in the region of zero recombination.[unreadable] [unreadable] 2. Spinal Muscular Atrophy: Degeneration of lower motor neurons in the spinal cord that causes neurogenic muscle atrophy, the so-called spinal muscular atrophies (SMAs), are a large category of inherited disorders.